tetano
Editor, Senior Moderator
Immunity
. 2023 Sep 26;S1074-7613(23)00408-9.
doi: 10.1016/j.immuni.2023.09.003. Online ahead of print. Antibodies targeting a quaternary site on SARS-CoV-2 spike glycoprotein prevent viral receptor engagement by conformational locking
Lihong Liu[SUP] 1 [/SUP], Ryan G Casner[SUP] 2 [/SUP], Yicheng Guo[SUP] 3 [/SUP], Qian Wang[SUP] 3 [/SUP], Sho Iketani[SUP] 3 [/SUP], Jasper Fuk-Woo Chan[SUP] 4 [/SUP], Jian Yu[SUP] 3 [/SUP], Bernadeta Dadonaite[SUP] 5 [/SUP], Manoj S Nair[SUP] 3 [/SUP], Hiroshi Mohri[SUP] 3 [/SUP], Eswar R Reddem[SUP] 2 [/SUP], Shuofeng Yuan[SUP] 4 [/SUP], Vincent Kwok-Man Poon[SUP] 4 [/SUP], Chris Chung-Sing Chan[SUP] 4 [/SUP], Kwok-Yung Yuen[SUP] 4 [/SUP], Zizhang Sheng[SUP] 3 [/SUP], Yaoxing Huang[SUP] 3 [/SUP], Jesse D Bloom[SUP] 6 [/SUP], Lawrence Shapiro[SUP] 7 [/SUP], David D Ho[SUP] 8 [/SUP]
Affiliations
SARS-CoV-2 continues to evolve, with many variants evading clinically authorized antibodies. To isolate monoclonal antibodies (mAbs) with broadly neutralizing capacities against the virus, we screened serum samples from convalescing COVID-19 patients. We isolated two mAbs, 12-16 and 12-19, which neutralized all SARS-CoV-2 variants tested, including the XBB subvariants, and prevented infection in hamsters challenged with Omicron BA.1 intranasally. Structurally, both antibodies targeted a conserved quaternary epitope located at the interface between the N-terminal domain and subdomain 1, uncovering a site of vulnerability on SARS-CoV-2 spike. These antibodies prevented viral receptor engagement by locking the receptor-binding domain (RBD) of spike in the down conformation, revealing a mechanism of virus neutralization for non-RBD antibodies. Deep mutational scanning showed that SARS-CoV-2 could mutate to escape 12-19, but such mutations are rarely found in circulating viruses. Antibodies 12-16 and 12-19 hold promise as prophylactic agents for immunocompromised persons who do not respond robustly to COVID-19 vaccines.
Keywords: N-terminal domain; Omicron; SARS-CoV-2; broadly neutralizing antibody; quaternary epitope; subdomain 1.
. 2023 Sep 26;S1074-7613(23)00408-9.
doi: 10.1016/j.immuni.2023.09.003. Online ahead of print. Antibodies targeting a quaternary site on SARS-CoV-2 spike glycoprotein prevent viral receptor engagement by conformational locking
Lihong Liu[SUP] 1 [/SUP], Ryan G Casner[SUP] 2 [/SUP], Yicheng Guo[SUP] 3 [/SUP], Qian Wang[SUP] 3 [/SUP], Sho Iketani[SUP] 3 [/SUP], Jasper Fuk-Woo Chan[SUP] 4 [/SUP], Jian Yu[SUP] 3 [/SUP], Bernadeta Dadonaite[SUP] 5 [/SUP], Manoj S Nair[SUP] 3 [/SUP], Hiroshi Mohri[SUP] 3 [/SUP], Eswar R Reddem[SUP] 2 [/SUP], Shuofeng Yuan[SUP] 4 [/SUP], Vincent Kwok-Man Poon[SUP] 4 [/SUP], Chris Chung-Sing Chan[SUP] 4 [/SUP], Kwok-Yung Yuen[SUP] 4 [/SUP], Zizhang Sheng[SUP] 3 [/SUP], Yaoxing Huang[SUP] 3 [/SUP], Jesse D Bloom[SUP] 6 [/SUP], Lawrence Shapiro[SUP] 7 [/SUP], David D Ho[SUP] 8 [/SUP]
Affiliations
- PMID: 37776849
- DOI: 10.1016/j.immuni.2023.09.003
SARS-CoV-2 continues to evolve, with many variants evading clinically authorized antibodies. To isolate monoclonal antibodies (mAbs) with broadly neutralizing capacities against the virus, we screened serum samples from convalescing COVID-19 patients. We isolated two mAbs, 12-16 and 12-19, which neutralized all SARS-CoV-2 variants tested, including the XBB subvariants, and prevented infection in hamsters challenged with Omicron BA.1 intranasally. Structurally, both antibodies targeted a conserved quaternary epitope located at the interface between the N-terminal domain and subdomain 1, uncovering a site of vulnerability on SARS-CoV-2 spike. These antibodies prevented viral receptor engagement by locking the receptor-binding domain (RBD) of spike in the down conformation, revealing a mechanism of virus neutralization for non-RBD antibodies. Deep mutational scanning showed that SARS-CoV-2 could mutate to escape 12-19, but such mutations are rarely found in circulating viruses. Antibodies 12-16 and 12-19 hold promise as prophylactic agents for immunocompromised persons who do not respond robustly to COVID-19 vaccines.
Keywords: N-terminal domain; Omicron; SARS-CoV-2; broadly neutralizing antibody; quaternary epitope; subdomain 1.